Peelable pouch for transdermal patch and method for packaging

ABSTRACT

A peelable pouch comprises a substantially flat enclosure formed by first and second opposing flexible plies. A seat extends along at least a portion of a perimeter of the opposing plies. A flat, flexible transdermal patch is disposed in the enclosure and includes a bioactive agent dissolved in a layer of adhesive. A release liner is removably attached over the layer of adhesive, with the patch and the release liner together being sufficiently resilient so as to generate a spring force when displaced out of the flat configuration. The first and the second plies each being separable along the seal and displaceable out of the flat configuration. The spring force generated by the patch and the release liner being sufficient to overcome an adhesive force created by the adhesive between the patch and one of the plies.

This application is a continuation of U.S. patent application Ser. No.13/036,791, filed Feb. 28, 2011, issued as U.S. Pat. No. 8,623,404;which in turn is a divisional of U.S. patent application Ser. No.11/645,115, filed Dec. 21, 2006, issued as U.S. Pat. No. 7,921,999;which is a continuation-in-part of U.S. patent application Ser. No.10/996,476, filed Nov. 24, 2004, abandoned; which is a continuation ofU.S. patent application Ser. No. 10/321,405, filed Dec. 16, 2002,abandoned; which claims benefit of U.S. Provisional Patent ApplicationSer. No. 60/343,475, filed Dec. 20, 2001; all of which are incorporatedherein in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to peelable pouches for storageof transdermal patches, and methods for packaging objects or transdermalpatches.

2. Related Art

Transdermal systems often include medicine or another bioactive agentthat is absorbed by the user's skin over a period of time. A typicaltransdermal system can include an adhesive skin patch containingmedicine that passes from the patch and through the user's skin. Suchpatches often are provided in a package formed of a pair of plies ofmaterial that are sealed together about their perimeters. A thin spaceis disposed between the sealed plies in which the transdermal patch islocated.

One disadvantage with transdermal systems, or the packaging thereof, isthe difficulty in removing the patch from the package for use.Typically, the perimeter of the package is scored or notched near acorner to facilitate breaking or tearing the sealed plies and openingthe package. The user can grasp the package adjacent either side of thescore or notch, and tear off a portion of the package to reveal the thinspace with the transdermal patch therein.

It will be appreciated that such transdermal patches often include anadhesive used to affix the patch to the user's skin. Over time, aminimal amount of such adhesive can seep out about a perimeter of thepatch, causing the patch itself to adhere to an inner surface of thepackage. Thus, as the user tears off a portion of the package to revealthe thin space and patch therein, the patch can be adhered to a surfaceof the package instead of being freely exposed within the space,resisting convenient removal of the patch. Although the packagingtypically includes an inner surface of foil, or other “non-stick”surface such as a polymer coating, to resist adherence of the patch tothe packaging, the adhesive often is capable of lightly adhering to suchsurfaces, or is capable of providing sufficient adherence to thwart orprevent removal of the patch.

It also will be appreciated that such patches, and thus such packages,can be small enough that the thin space therein is small enough toprevent or hinder the user from inserting his or her fingers andgrasping the patch. In addition, as stated above, the patch can becomeadhered to the inner surface the package, thus further preventing orresisting the user's attempt to grasp the patch, even if sufficientspace exists to insert fingers.

In addition, the user often must engage in further operations to furtheropen the package and retrieve the patch. For example, after having tornthe first portion of the package to obtain access to the space and thepatch, the user often must further tear the package in order to increasethe opening to the space, or further reveal the patch, in order toincrease access to grasp the patch or separate it from the inner surfaceof the package. Such further manipulation of the packaging increases therisk of molesting or damaging the patch.

Another disadvantage with such transdermal systems, or packaging, isthat the tear method of opening the package increases the risk oftearing the package across the transdermal patch itself, thus tearing ormolesting the patch.

Another disadvantage with such transdermal systems is that packagingconfigured for one type of transdermal system may not be sufficient topackage another. For example, one package configured to prevent leakageof a first type of medicine may not sufficiently prevent leakage of asecond type of medicine because such packaging may not contain thesecond type of medicine.

SUMMARY OF THE INVENTION

The invention provides a peelable pouch, including a substantially flatenclosure formed by first and second opposing flexible plies. A seal canextend along at least a portion of a perimeter of the opposing plies. Aflat, flexible transdermal patch can be disposed in the enclosure, thepatch including a bioactive agent dissolved in a layer of adhesive. Arelease liner can be removably attached over the layer of adhesive. Thepatch and the release liner can together be sufficiently resilient so asto generate a spring force when displaced out of the flat configuration.The first and the second plies can each be separable along the seal andcan be displaceable out of the flat configuration. The spring forcegenerated by the patch and the release liner can be sufficient toovercome an adhesive force created by the adhesive between the patch andone of the plies.

In accordance with another aspect of the invention, a peelable pouch isprovided, including a substantially flat enclosure formed by first andsecond opposing flexible plies. A seal can extend along at least aportion of a perimeter of the opposing plies and can couple the plies toone another. A flexible transdermal patch can be disposed in theenclosure, the patch including a bioactive agent dissolved in a layer ofadhesive. A release liner can be removably attached over the layer ofadhesive. The patch and the release liner can together be sufficientlyrigid so as to at least partially resist bending, and can besufficiently resilient so as to return to a substantially flatorientation after being bent out of the flat configuration. The firstand the second plies can each be separable along the seal anddisplaceable out of the flat configuration.

In accordance with another aspect of the invention, an oxybutyninmedicine system is provided, including first and second opposingflexible plies forming an enclosure. A seal can extend along at least aportion of a perimeter of the opposing plies with an enclosed cavitybetween the plies. First and second opposing tabs, formed by a portionof the respective first and second opposing plies, can extend beyond theseal. An oxybutynin transdermal patch can be disposed in the enclosedcavity between the first and second opposing plies. The transdermalpatch can include i) a substrate; ii) an adhesive layer disposed on thesubstrate and configured to adhere the substrate to a users skin; iii)oxybutynin dissolved in the adhesive layer; and iv) a release liner,removably disposed over the adhesive layer and the oxybutynin dissolvedtherein. The oxybutynin, and/or a permeation enhancer, can interact withthe adhesive layer and can cause the adhesive therein to i) losecohesion, ii) seep beyond a perimeter of the patch, and iii) adhere toat least one of the two plies of the pouch. The seal can include apolyacrylonitrile copolymer resin. The first and second opposingflexible plies can have: i) a closed configuration in which a majorityof the two plies are disposed in a planar layer; and ii) an openconfiguration in which at least a portion of the two plies are separatedalong the seal and pulled out of the planar layer and back across theplanar layer to present the oxybutynin transdermal patch between the twoplies.

There has thus been outlined, rather broadly, relatively importantfeatures of the invention so that the detailed description thereof thatfollows may be better understood, and so that the present contributionto the art may be better appreciated. Other features of the presentinvention will become clearer from the following detailed description ofthe invention, taken with the accompanying drawings and claims, or maybe learned by the practice of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a front view of a preferred embodiment of a peelable pouch inaccordance with the present invention;

FIG. 2 is a front view of the peelable pouch of FIG. 1 with one ply ofthe pouch removed to reveal a transdermal patch therein;

FIG. 3 is a side view of the peelable pouch of FIG. 1 shown in a firstclosed configuration;

FIG. 4A is a side view of the peelable pouch of FIG. 1, shown in anintermediate configuration as the plies are separated from one another;

FIG. 4B is a side view of the peelable pouch of FIG. 4A, shown in asecond, open configuration presenting the transdermal patch;

FIG. 5 is a front view of the peelable pouch of FIG. 1 shown in thesecond open configuration presenting the transdermal patch;

FIG. 6 is a schematic cross sectional view of a ply and a transdermalpatch;

FIG. 7 is a front view of another embodiment of a peelable pouch inaccordance with the present invention;

FIG. 8 is a front view of the peelable pouch of FIG. 7 with one ply ofthe pouch removed to reveal a transdermal patch therein;

FIGS. 9 a-9 h are front views of other embodiments of a peelable pouchin accordance with the present invention;

FIG. 10 is a schematic view of a machine and method for packagingtransdermal patches in accordance with the present invention; and

FIG. 11 is a schematic view of another machine and method for packagingtransdermal patches in accordance with the present invention.

DETAILED DESCRIPTION

Before the present invention is disclosed and described, it should beunderstood that this invention is not limited to the particularstructures, process steps, or materials disclosed herein, but isextended to equivalents thereof as would be recognized by those ofordinarily skilled in the relevant arts. It should also be understoodthat terminology employed herein is used for the purpose of describingparticular embodiments only and is not intended to be limiting in anyway.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a” and “the” include plural referents,unless the context clearly dictates otherwise. Thus, for example,reference to a “medicament” includes one or more of such medicaments.

DEFINITIONS

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set forthbelow.

“Topical formulation” means a composition in which the drug may beplaced for direct application to a skin surface and from which aneffective amount of drug is released. Examples of topical formulationsinclude but are not limited to ointments, creams, gels, transdermalpatches, sprays, vaginal rings, and pastes.

“Transdermal” refers to the route of administration that facilitatestransfer of a drug through a skin surface wherein a transdermalcomposition is administered to the skin surface.

Transdermal administration can be accomplished by applying, pasting,rolling, attaching, pouring, pressing, rubbing, etc., of a transdermalpreparation onto a skin surface. These and additional methods ofadministration are well-known in the art.

“Transdermal delivery system,” “transdermal patches” or simply “patches”refer to a matrix or liquid reservoir type of delivery device which isused to transdermally deliver defined doses of a substance, over aspecific application period.

One example of a transdermal patch for administering oxybutynin inaccordance with this invention is a matrix-type patch which comprises anocclusive backing that is impermeable to the oxybutynin and defines theface or top surface of the patch and a solid or semisolid matrix layercomprised of a homogeneous blend of the oxybutynin, a polymeric pressuresensitive adhesive carrier, and optionally one or more skin permeationenhancers. Matrix patches are known in the art of transdermal drugdelivery. Examples without limitation, of adhesive matrix transdermalpatches are those described or referred to in U.S. Pat. Nos. 5,122,383and 5,460,820, which are incorporated by reference in their entirety.

A transdermal patch for administering male testosterone such asAndroderm™, in accordance with this invention, is a liquid reservoirsystem (LRS) type patch which comprises male testosterone, and otheroptional ingredients such as a permeation enhancer, in a carriervehicle. The carrier vehicle comprises a fluid of desired viscosity,such as a gel or ointment, which is formulated for confinement in areservoir having an impermeable backing and a skin contacting permeablemembrane, or membrane adhesive laminate providing diffusional contactbetween the reservoir contents and the skin. For application, a peelablerelease finer is removed and the patch is attached to the skin surface.LRS patches are known in the art of transdermal drug delivery. Exampleswithout limitation, of LRS transdermal patches are those described orreferred to in U.S. Pat. Nos. 4,849,224 and 4,983,395, which areincorporated by reference in their entirety.

“Skin,” “skin surface,” “derma,” “epidermis,” and similar terms are usedinterchangeably herein, and refer to not only the outer skin of asubject comprising the epidermis, but also to mucosal surfaces to whicha drug composition may be administered. Examples of mucosal surfacesinclude the mucosal of the respiratory (including nasal and pulmonary),oral (mouth and buccal), vaginal, introital, labial, and rectalsurfaces. Hence the terms “transdermal” encompasses “transmucosal” aswell.

The terms “formulation” and “composition” are used interchangeablyherein. The terms “pharmaceutical” and “drug” are also usedinterchangeably to refer to a pharmacologically active substance orcomposition. “Bioactive agent”, “medicine”, “medication”, “drug”,“prescription” and similar terms are used interchangeably herein. Theseterms of art are well-known in the pharmaceutical and medicinal arts.

“Permeation enhancer” refers to anything used to assist the transdermalformulation to penetrate the skin. A wide variety of skin penetrationenhancers are suitable with a transdermal device being used in the pouchof the present invention. The specific enhancer used may depend largelyon the particular transdermal formulation to be employed and may bedetermined by one of ordinary skill in the art without undueexperimentation by considering various factors such as the bioactiveagent or drug to be delivered, the specific pharmaceutically acceptablecarrier to be used, etc. An index of permeation enhancers is disclosedby David W. Osborne and Jill J. Henke, in their publication entitled“Skin Penetration Enhancers Cited in the Technical Literature,”published in Pharmaceutical Technology (June 1998), and is incorporatedherein by reference.

Examples of suitable penetration enhancers of the present inventioninclude, without limitation: fatty acids, fatty acid esters, fattyalcohols, fatty acid esters of lactic acid or glycolic acid and theirsalts, amides, amines, pyrrolidones, glycerol triesters, terpenes,classical surfactants, azocyclic compounds, organic acids, complexingagents, biologics and mixtures thereof.

The term “ply” or “plies” refers to one or more layers or sheets ofmaterial.

The term “seal” refers to a closure to block access and that must bebroken to gain access. Such a seal can be formed chemically,mechanically, or both chemically and mechanically. An example of a sealincludes adhering portions or plies of the pouch together by an adhesiveor other means. The seal can include resins or resin compositions, suchas vinyl resins, polyethylene resin, hydroxyl modified, vinylchloride-acetate, thermoplastic copolymer resin; thermoplastic materialssuch as polyethylene, polyvinyl chloride; a polyvinyl acetal such aspolyvinyl butyral, polyvinyl acetal, polyvinyl formal; a polyester suchas polyalkylene terephthalate (such as Mylar™); polyvinyl alcohol,methyl cellulose, sodium carboxymethylhydroxyethyl cellulose,polyethylene glycol, polyvinyl acetate-chloride copolymer,polyvinylidene chloride, polypropylene, polyimide, or fluorinatedethylene-propylene copolymer.

The seal can be formed by applying heat and/or pressure to the pouch orplies, causing the adhesive or other material to adhere the pliestogether, and seal the pouch. In addition, the seal can be formed byultra-sonic welding. In addition, the seal can be corrugated orembossed.

The term “tab” or “tabs” refers to a flap or appendage for grasping andpulling. For example, a portion of the ply or pouch can form a tab.

As used herein, the term “substantially” refers to the complete ornearly complete extent or degree of an action, characteristic, property,state, structure, item, or result. For example, an object that is“substantially” enclosed would mean that the object is either completelyenclosed or nearly completely enclosed. The exact allowable degree ofdeviation from absolute completeness may in some cases depend on thespecific context. However, generally speaking the nearness of completionwill be so as to have the same overall result as if absolute and totalcompletion were obtained. The use of “substantially” is equallyapplicable when used in a negative connotation to refer to the completeor near complete lack of an action, characteristic, property, state,structure, item, or result. For example, a composition that is“substantially free of” particles would either completely lackparticles, or so nearly completely lack particles that the effect wouldbe the same as if it completely lacked particles. In other words, acomposition that is “substantially free of” an ingredient or element maystill actually contain such item as long as there is no measurableeffect thereof.

As used herein, the term “about” is used to provide flexibility to anumerical range endpoint by providing that a given value may be “alittle above” or “a little below” the endpoint.

Distances, angles, forces, weights, amounts, and other numerical datamay be expressed or presented herein in a range format. It is to beunderstood that such a range format is used merely for convenience andbrevity and thus should be interpreted flexibly to include not only thenumerical values explicitly recited as the limits of the range, but alsoto include all the individual numerical values or sub-ranges encompassedwithin that range as if each numerical value and sub-range is explicitlyrecited. As an illustration, a numerical range of “about 1 inch to about5 inches” should be interpreted to include not only the explicitlyrecited values of about 1 inch to about 5 inches, but also includeindividual values and sub-ranges within the indicated range. This sameprinciple applies to ranges reciting only one numerical value and shouldapply regardless of the breadth of the range or the characteristicsbeing described.

As used herein, a plurality of items, structural elements, compositionalelements, and/or materials may be presented in a common list forconvenience. However, these lists should be construed as though eachmember of the list is individually identified as a separate and uniquemember. Thus, no individual member of such list should be construed as ade facto equivalent of any other member of the same list solely based ontheir presentation in a common group without indications to thecontrary.

THE INVENTION

As illustrated in FIGS. 1-5, a peelable pouch 14 in accordance with thepresent invention is shown for packaging objects. Transdermal patchesare one example of a field that may benefit from use of such a peelablepouch 14. Other fields that may benefit from the use of such a peelablepouch 14 include surgical and medical implements, adhesive bandages,syringes, etc. The peelable pouch 14 may form part of a transdermalmedicine system 10 with a transdermal patch 18 disposed within thepeelable pouch 14.

Bioactive agents or medicines are commonly administered with transdermalpatches. In one aspect, the contents of the pouch of the presentinvention may be a transdermal patch. A variety of transdermal patchesare known to those of ordinary skill in the art. For example, U.S. Pat.Nos. 5,122,383 and 5,460,820, which are incorporated by reference intheir entirety, disclose various adhesive matrix patches. Further, U.S.Pat. Nos. 4,849,224 and 4,983,395, which are incorporated by referencein their entirety, disclose various Liquid Reservoir System (LRS) typepatches. Each of these general types of patches, as well as others,utilizes various structural components, which are known to those skilledin the art.

As illustrated in FIG. 6, by way of example without limitation, in thecase of an adhesive matrix patch 18, an adhesive layer 19 is disposed ona substrate or distal backing 20. The distal backing can be laminated toa polymer layer (not shown). Such a distal backing defines the side ofthe matrix patch that faces the environment, i.e., distal to the skin ormucosa. The backing layer functions to protect the matrix polymer layerand drug/enhancer composition and to provide an impenetrable layer thatprevents loss of drug to the environment. Thus, the material chosen forthe backing should be compatible with the polymer layer, drug, andenhancer if any, and should be minimally permeable to any components ofthe matrix patch. Advantageously, the backing can be opaque to protectcomponents of the matrix patch from degradation from exposure toultraviolet light. Furthermore, the backing should be capable of bindingto and supporting the polymer layer, yet should be pliable enough toaccommodate the movements of a person using the matrix patch.

Suitable materials for the backing include, but are not limited to:metal foils, metalized polyfoils, composite foils or films containingpolyester such as polyester terephthalate, polyester or aluminizedpolyester, polytetrafluoroethylene, polyether block amide copolymers,polyethylene methyl methacrylate block copolymers, polyurethanes,polyvinylidene chloride, nylon, silicone elastomers, rubber-basedpolyisobutylene, styrene, styrene-butadiene and styrene-isoprenecopolymers, polyethylene, and polypropylene. In one aspect of theinvention, the backing layer may have a thickness of about 0.0005 to0.01 inch.

Further, a release layer or release liner 21 may be temporarily providedupon the proximal side (side to adhere to the skin) of the adhesivelayer. Such a liner provides many of the same functions as the backinglayer (20) prior to adhesion of the patch to the skin (the release layeris removed prior to attaching the patch to the skin). In use, therelease liner is peeled from the adhesive layer just prior toapplication, and then is discarded. The release liner can be made of thesame materials as the backing layer, or other suitable films coated withan appropriate release surface. Thus, while the backing layer/substrateremains as an integral part of the patch (whether or not the patch isattached to the skin), the release layer must be removed prior toattaching the patch to the skin.

A wide variety of materials known to those skilled in the art oftransdermal drug delivery may be used as pharmaceutically acceptablecarriers for a transdermal patch. In one aspect the carrier may be abiocompatible polymer. In another aspect, the carrier may be anadhesive. In the case of an adhesive matrix patch, the carrier may be abiocompatible adhesive polymer. The carrier, in some aspects, maycontain the drug to be transdermally delivered and a penetrationenhancer and other ingredients, such as emollients, etc. In the case ofa Liquid Reservoir System (LRS) patch, the carrier forms a gel, or otherviscous form suitable for use in an LRS patch, as is known in the art.Such a viscous carrier may contain both the drug to be transdermallydelivered as well as a penetration enhancer and other ingredients.

In one aspect, the pressure-sensitive adhesive of the pharmaceuticallyacceptable carrier is suitable for long-term (e.g., greater than 1 day,about 3-4 days, or for longer periods such as 1-4 weeks) contact withthe skin. In another aspect, the pressure-sensitive adhesive of thecarrier is suitable for a short-term administration (e.g., for a fewminutes to a few hours, less than or equal to 1 day). Such adhesivesmust be physically and chemically compatible with the particular drugand enhancer, and with any carriers and/or vehicles or other additivesincorporated into the drug/enhancer composition. In one aspect of theinvention, the adhesives of the pharmaceutically acceptable carrierinclude, without limitation, acrylic adhesives including cross-linkedand uncross-linked acrylic copolymers; vinyl acetate adhesives; naturaland synthetic rubbers including polyisobutylenes, neoprenes,polybutadienes, and polyisoprenes; ethylenevinylacetate copolymers;polysiloxanes; polyacrylates; polyurethanes; plasticized weightpolyether block amide copolymers, and plasticized styrene-rubber blockcopolymers or mixtures thereof. In yet another aspect of the invention,contact adhesives for use in the pharmaceutically acceptable carrierlayer are acrylic adhesives, such as DuroTak 87-2888 adhesive (NationalStarch & Chemical Co., Bridgewater, N.J.); and polyisobutylene adhesivessuch as ARcareJ MA-24 (Adhesives Research, Glen Rock, Pa.) and ethylenevinyl acetate copolymer adhesives.

While the pharmaceutically acceptable carrier of an LRS patch may be ofany suitable viscous material known to those skilled in the art oftransdermal drug delivery, in one aspect of the present invention, thepharmaceutically acceptable carrier of the liquid reservoir forms a gel.

In addition to containing the drug and penetration enhancer, thepharmaceutically acceptable carrier may comprise a number of otheradditives, such as diluents, excipients, emollients, plasticizers, skinirritation reducing agents, or a mixture thereof. These types ofcomponents, as well as others not specifically recited, are well knownin the art for inclusion in various transdermal formulations, and may beadded as desired to the transdermal drug delivery system of the presentinvention in specific types and amounts in order to achieve a desiredresult.

For example, suitable diluents can include mineral oil, low molecularweight polymers, plasticizers, and the like. Many transdermal drugdelivery formulations have a tendency to cause skin irritation afterprolonged exposure to the skin, thus addition of a skin irritationreducing agent aids in achieving a composition that is better toleratedby the skin. In one aspect, the skin irritation reducing agent may beglycerin, as disclosed in U.S. Pat. No. 4,855,294, which is incorporatedby reference in its entirety.

As described above, such patches are commonly provided in tear packagesthat are ripped or torn open to obtain access to the patch.

It will be appreciated that while the release layer covers most of thesurface of the adhesive layer, the patch or adhesive layer can have aperimeter that is exposed to the surrounding environment. The exposedperimeter sometimes allows a minimal amount of the adhesive to escapefrom the patch beyond the release liner. The escaped adhesive can causethe patch to adhere to the interior of the packaging, thus thwarting orhindering efforts to remove the patch from the packaging for use.

In addition, it has been discovered that certain bioactive agents ormedicines, or other ingredients thereof, can cause the adhesive in whichit is dissolved to lose cohesion, and seep out of the perimeter of thepatch (between the patch and the substrate/backing layer), to a greaterextent, thus further aggravating or exasperating the problem of seepageof adhesive. For example, it has been discovered that oxybutynin, and/ora permeation enhancer, causes certain adhesives to lose cohesion andseep or flow more so than other bioactive agents or medicines. Thus, ithas been observed that oxybutynin transdermal patches have more frequentoccurrences of seepage, and thus adherence to packaging, and/or greateradhesion to the packaging. As discussed above, such adhesion hindersremoval of the patch from the packaging, and can result in molestationof the patch as the user rips, tears, or otherwise mutilates thepackaging to remove the patch.

In one aspect, the peelable pouch 14 of the present inventionadvantageously is configured to facilitate opening and removal of atransdermal patch contained therein, and to accommodate the tendency oftransdermal patches, such as those with oxybutynin, to adhere to thepackaging. Referring again to FIGS. 1 & 2, the peelable pouch 14includes first and second opposing plies 22 and 24 forming an enclosure28. The first and second plies 22 and 24 can be separate plies, orseparate sheets of material. Alternatively, the plies 22 and 24 may bepart of a single sheet of material, folded to have the opposing plies.

A seal 32 is formed along at least a portion of a perimeter of the plies22 and 24 sealing at feast a portion of the plies together. In oneaspect, the seal 32 extends along nearly the entire perimeter of theplies. An enclosed cavity 36 is formed between the opposing plies 22 and24, and the seal 32. The transdermal patch 18 is received within theenclosure 28 or cavity 36. The peelable pouch 14, enclosure 28, and/orplies 22 and 24 have a closed configuration, as shown in FIGS. 1 and 3,in which the pouch 14 is sealed and the patch 18 is contained within theenclosure 28.

The transdermal patch 18 preferably is flexible to conform to thecontours of the user's body or skin, but initially is flat to reducespace for packaging and shipping. In addition, the plies 22 and 24 andthe enclosure 28 may define a substantially or mostly flat, planar layercontaining the patch 18, and the plies 22 and 24. In one aspect, thepatch 18 and the plies 22 and 24 have a rectangular or square shape tofacilitate manufacturing and packaging, but it is contemplated that thepatch and plies can have any desired shape.

In one aspect of the invention, portions of the plies 22 and 24 canextend beyond the perimeter or the seal 32 to form first and secondopposing tabs 40 and 42. The tabs 40 and 42 are sized large enough tofacilitate being grasped by the user. Thus, the tabs 40 and 42 can havea size approximately equal to the tips of a user's fingers. As statedabove, the seal 32 can extend around a majority of the perimeter of theplies 22 and 24 or the enclosure 28. A portion 46 of the seal 32,however, can be indented from, or formed away from, a portion of theperimeter of the plies 22 and 24 to form the tabs 40 and 42. In oneaspect, the portion 46 of the seal 32 transverses a corner of the plies22 and 24, leaving the corners of the plies unsealed, to form the tabs40 and 42.

As stated above, typical packaging can make removing the patch difficultand increases the risk of molesting the patch. In addition, patchesoften have a tendency to adhere to one side of the packaging,frustrating removal of the patch. The peelable pouch 14, enclosure 28,and/or plies 22 and 24 of the present invention advantageously have anopen configuration, as shown in FIGS. 4 and 5, in which portions 50 and52 of the plies 22 and 24 are separated along the seal 32 in oppositedirections, and the transdermal patch 18 is presented extending from thepouch 14 or enclosure 28, between the plies 22 and 24.

To open the pouch 14, the user grasps the opposing tabs 40 and 42 withfingers of opposite hands, and pulls the tabs 40 and 42, and thus theplies 22 and 24, in a natural direction, which is outwardlyapproximately perpendicularly or orthogonally to the planar layer of theplies 22 and 24, indicated by arrows 56 and 58 in FIG. 4A. As the userpulls on the tabs 40 and 42, the plies 22 and 24 separate from oneanother along the seal 32, and the opened portions 50 and 52 are formed.

As the user continues to pull, the tabs 40 and 42, and the open portions50 and 62, extend back across the pouch 14 or plies 22 and 24. Theinventor has found that the outward and backward movement of the openportions 50 and 52 of the plies 22 and 24 tends to cause the openportions 50 and 52 to pull away from any portions of the patch 18 thatmay be adhered to one or both of the plies.

Although the patch 18 can be flexible, it also is resilient enough todevelop a spring force if it is bent backwardly along with one of theplies, such that the developed spring force overcomes any adherence tothe ply, and causes the patch 18 itself to pull away from the plies, asshown in FIG. 4A. In this aspect of the invention, the plies 22, 24 canbe more flexible (or more easily bent) than the patch by itself. In thismanner, an operator can peel the ply away from the patch, without havingto touch the patch, by pulling one or both of the plies at a sharp anglerelative to the patch and separating the patch from the plies.

In addition, it is believed that the backward movement of the openportion 50 and 52 of the plies 22 and 24 is in a direction along theplane of the patch 18 where the patch is most rigid, causing the pliesto separate from the patch, rather than tending to bend the patch.Therefore, when the plies 22 and 24 are separated, a portion of thepatch 18 extends outwardly from the pouch 14, enclosure 28, and/or plies22 and 24, substantially in the planar layer, and presented between theplies 22 and 24 such that it can be easily grasped by the user.

This concept is illustrated schematically in the progression shown fromFIG. 3 to FIG. 4A to FIG. 4B. As shown in FIG. 3, initially the tabs 40,42 can be grasped by the user so that the user can separate the tabs,and thus the plies, along the seal. As shown in FIG. 4A, the initialseparation of the plies may result in the patch remaining adhered to oneof the plies and bending along with the ply. However, due to thedifference in rigidity between the patch and the ply, a restoring springforce (illustrated schematically by directional indicators 53) iscreated in the patch as it is bent with the ply. The spring force issufficient to cause the patch (together with the liner) to peel awayfrom the ply (that is being held by fingers of the user), resulting inthe patch being presented, in a “free” state, for removal by the userfrom between the plies.

The spring force created in the patch 18 can be induced in a number ofmanners. In one aspect of the invention, the material of the patchand/or the liner is selected to provide sufficient rigidity to overcomeany adhesion caused by adhesive leeching from the patch. In anotheraspect, a geometric configuration, including a width, of the patch canbe selected to provide the proper spring force for the adhesive beingused. The adhesive used can also be varied to ensure that the properrestoring spring force is provided.

In one embodiment of the invention, the patch is formed of an adhesivecontaining oxybutynin and a permeation enhancer, and apolyester-ethylene vinyl acetate backing layer with an overall thicknesson the order of 4 mils, and the liner is formed of a polyester materialwith a thickness on the order of 3 mils. The plies can be formed ofpaper, low-density polyethylene, foil, adhesive, and/or Barex with athickness on the order of 4 mils. In this embodiment, it has been foundthat spring force generated by deflecting or bending the patch issufficient to overcome any adhesive force applied when utilizing anadhesive material comprising hexamethyleneglycol dimethacrylate, 2-ethylhexylacrylate and N-vinyl pyrrolidone.

Generally, however, the patch will be presented between the plies thathave each been displaced outwardly from the patch, so that the patch isnot “stuck” to any one ply and need not be peeled by hand from theparticular ply. Attempting to peel the patch by hand from a ply to whichit is adhered is a procedure that can result in contamination of theuser's fingers, and can risk damaging the patch in the event the patchis relatively securely attached to the particular ply.

In accordance with one aspect of the present invention, the transdermalsystem can be an oxybutynin medicine system, and the transdermal patchcan be an oxybutynin transdermal patch. Oxybutynin can be used to treaturinary incontinence, or overactive bladder. The oxybutynin is dissolvedin the adhesive layer of the patch. As stated above, it has been foundthat oxybutynin, and/or the associated permeation enhancer or otheringredients, can cause the adhesive to lose cohesion, seep beyond aperimeter of the patch, and adhere to the plies of the pouch (but stillsatisfy its specifications with respect to the FDA). Thus, theconfiguration of the pouch 14 of the present invention is well suited tofacilitate opening.

Referring to FIG. 1, the seal 32 between the plies 22 and 24 of thepouch 14 for an oxybutynin patch can include a polyacrylontrilecopolymer resin, such as Barex® made by British Petroleum, because ithas been found to contain the oxybutynin in a satisfactory manner. Inaddition, referring to FIG. 6, the plies can be formed of a three-plylaminate including an outer layer 70 of coated paper, a core layer 72 offoil, and a laminate 74 of low density polyethylene (LDPE). The outerlayer of coated paper provides structural stiffness and a printablesurface. In one aspect, the outer layer is 26 lb. C1S paper. The corelayer of foil provides a barrier to moisture, gas, and light. Thepolyethylene layer provides adhesion between the paper and foil, andsupport for the foil. A layer 76 of the polyacrylontrile copolymerresin, such as Barex®, is disposed over the foil, attached with anadhesive layer, and provides chemical inertness as well as a sealingmedium.

In accordance with another aspect of the present invention, thetransdermal system can be an estradiol medicine system, and thetransdermal patch can be an estradiol transdermal patch. Estradiol, suchas Alora®, can be used in female hormone replacement therapy, and totreat osteoporosis. The plies can be formed of an outer layer of coatedpaper, a core layer of foil, and a laminate of polyethylene (PE). In oneaspect, the seal includes a layer of Surlyn® because it has been foundto adequately contain estradiol.

In accordance with another aspect of the present invention, thetransdermal system can be a liquid reservoir system (LRS), as opposed toa matrix patch, and can include male testosterone, such as Androderm™.Male testosterone can be used to treat male hypogonadism or testosteronedeficiency. Again, the plies can include an outer layer of coated paper,a core of foil, and a laminate of polyethylene (PE). The seal caninclude a low density polyethylene (LDPE) because it has been found toadequately contain Androderm™.

It is of course understood that other bioactive agents can beaccommodated. For example, the transdermal patch can include a femaletestosterone patch for treating women with a hormone replacement therapyregiment. As another example, the transdermal patch can include ananti-fungal agent for toenails or fingernails, such as fluconazole. Asanother example, the transdermal patch can be used in pain relief, andcan include medicines such as fentanyl, morphine, and others. In oneaspect of the invention, the bioactive agent can include pramipexole, adopamine agonist indicated for the treatment of the signs and symptomsof idiopathic Parkinson's disease.

In general, drugs for use in the present composition include therapeuticagents in all of the therapeutic areas including, but not limited to:antibiotics (including antimicrobials, antibacterials,antimycobacterials, antimalerials, antiamebics, anthelminics,antifungals, and antivirals), neoplastic agents, agents affecting theimmune response (including steroidal and non-steroidal anti-inflammatoryagents), blood calcium regulators, peptide and protein hormones, agentsuseful in glucose regulation, antithrombotics and hemostatics,antihyperlipidemic agents, thyromimetic and antithyroid drugs, antiulceragents, histamine receptor agonists and antagonists, inhibitors ofallergic response, local anesthetics, analgesics and analgesiccombinations, antipsychotics, anti-anxiety agents, antidepressantsagents, anorexigenics, bone-active agents, diagnostic agents, and amixture thereof. Additional examples include: antidiarrheals,antimigraine preparations, antimotion sickness agents, antinauseants,antiparkinsonism drugs, antipruritics, antipyretics, antispasmodics(including gastrointestinal, urinary, skeletal, and smooth-muscle),anticholinergics, sympathomimetics, xanthine derivatives, cardiovascularpreparations (including calcium channel blockers, beta-blockers,antiarrythmics, antihypertensives, diuretics, vasodilators includinggeneral coronary, peripheral and cerebral), central nervous systemstimulants including cough and cold preparations, decongestants,diagnostics, hormones, immunosuppressives, parasympatholytics,parasympathomimetics, sedatives, tranquilizers and mixtures thereof.

Examples of specific drugs include without limitation: antibiotics:amoxicillin, cloxacillin sodium, penicillin G potassium; antimicrobials:benzalkonium chloride, chlorohexidine, gluconate hexachlorophene;antibacterials: sulfabenzamide, sulfadiazine, sulfasalazine;antimycobacterials: chlofazimine, ethambutol, isoniazid; antimalerials:chloroquine hydrochloride, quinine sulfate, pyrimethamine; antiamebics:arsthinol, bialamicol, carbarsone; anthelminics: ivermectin, bithionol,piperazine; antifungals: clotrimazole, griseofulvin, miconazole;antivirals: acyclovir, foscarnet sodium, ribavirin; neoplastic agents:adriamycine, cyclophosphamide, methotrexate; immune response steroidalanti-inflammatory agents: hydrocortisone, dioxyanthranol, betamethasone;non-steroidal anti-inflammatory agents (NSAIDs): choline salicylate,diflunisal, ibuprofen, acetaminophen; blood calcium regulators:parathyroid hormone, calcifediol, calcitonin; peptide and proteinhormones: insulin, glucagon, vasopressin; glucose regulators:tolazamide, tolbutamide, chlorpropamide; antithrombotics: aspirin,sulfinpyrazone, dipyridamole; hemostatics: thrombin, microfibrillarcollagen, absorbable gelatin powder; antihyperlipidemic agents:pravastatin sodium, simvastatin, clinofibrate; thyromimetic andantithyroid drugs: methimazole, propylthiouracil, potassium iodide;antiulcer agents: metoclopramide, histidine hydrochloride, famotidine;histamine receptor agonists and antagonists: astemizole, clemastinefumarate, cyclizine; allergic response inhibitors: astemizole,clemastine fumarate, diphenhydramine hydrochloride; local anesthetics:chloroprocaine hydrochloride, lidocaine hydrochloride, lidocaine base,procaine hydrochloride; analgesics and analgesic combinations:acetaminophen, aspirin, ibuprofen; antipsychotics: acetophenazinemaleate, chlorprothixene, droperidol; anti-anxiety agents:diphenhydramine, phenobarbital, chlordiazepoxide; anti-depressants:amitriptyline hydrochloride, amoxapine, fluoxetine hydrochloride;anorexigenics: amphetamine, methamphetamine, chlorphentermine;bone-active agents: parathyroid hormone, calcitonin; diagnostic agents:benzylpeniclloyl polylysine, iocetamic acid, aminohippurate sodium;antidiarrheals: diphenoxylate hydrochloride, loperamide hydrochloride,fennel oil; antimigraine preparations: dihydroergotamine mesylate,ergotamine tartrate, methysergide maleate, sumatriptin succinate;antimotion sickness agents: buclizine hydrochloride, diphenidol,meclizine hydrochloride; antinauseants: benzquinamide hydrochloride,dronabinol, dimenhydrinate; antiparkinsonism drugs: amantadinehydrochloride, pramipexole, ropinirole, rotigotine benztropine mesylate,biperiden hydrochloride; antipruritics: camphor, menthol, pramoxine;antipyretics: acetaminophen, aspirin, ibuprofen; antispasmodics(including gastrointestinal, urinary, skeletal and smooth-muscle):flavoxate, flavoxate hydrochloride, ethaverine hydrochloride, oxybutyninchloride, dicyclomine; anti-cholinergics: propantheline, oxybutynin,oxybutynin hydrochloride, adiphenine hydrochloride, aminopentamide,atropine; sympathomimetics: dopamine hydrochloride, epinephrine,ephedrine sulfate; xanthine derivatives: caffeine, theophylline,aminophylline; calcium channel blockers: amlodipine, felodipine,isradipine, diltiazem, nifedipine; beta blockers: propanolol, pindolol,labetalol, betaxolol; anti-arrythmics: procainamide, prajmaline,disopyramide; antihypertensives: clonidine hydrochloride, clonidinebase, guanabenz acetate, methyldopa; diuretics: ammonium chloride,mannitol, urea, hydrochlorothiazide, bumetanide; vasodilators: (general)diazoxide, minoxidil, pinacidil; (Coronary) amotriphene, bendazol,benfurodil hemisuccinate; (Peripheral) bamethan, bencyclane,betahistine; (Cerebral) bencyclane, cinnarizine, citicoline; centralnervous system (CNS) stimulants cough and cold preparations:dextromethorphan hydrobromide; decongestants: pseudoephedrinehydrochloride, diphenhydramine hydrochloride; chlorpheniramine maleate;hormones: estradiol, norelgestromin, corticosteroids, hydrocortisone;testosterone, progesterone; immunosuppressives: cyclosporin, mizoribine,brequinar sodium; parasympatholytics: atropine sulfate, belladonna,cyclopentolate hydrochloride; parasympathomimetics: pyridostigmine,physostigmine, scopolamine; sedatives: buspirone hydrochloride, chloralhydrate, disulfuram; tranquilizers: chloropromazine, promazine,fluphenzaine, other CNS stimulants: methylphenidate, cholinergics:rivastigmine.

In some aspects, the drug may be oxybutynin, buspirone, fentanyl,testosterone, progestin, estradiol, propentofylline, or a mixturethereof. It should be appreciated that one or more of these and otherdrugs described herein exist in many pharmaceutically acceptable salts.Examples of such salts include those generated by using inorganic agents(i.e., inorganic cations such as sodium, potassium, calcium, etc., andinorganic anions such as chloride, bromide, etc.,) and organic agents(i.e., organic cations such as piperazinyl, triazinyl, etc., and organicanions such as citrates, tartarates, tosylates, etc). In addition, thesedrugs are also present as polymorphs and/or isomers. Examples ofpolymorphs include monohydrates, dihydrates, hemi-hydrates, etc., aswell those high-melting and low-melting polymorphs. These polymorphs canbe characterized using X-ray crystallographic techniques or otherwell-known techniques in the art. Examples of isomers include geometricand optical isomers. Further, the pharmaceutical art has recognized thatsuch salts, isomers, and polymorphs, as well as prodrugs, analogs, andmetabolites for these drugs can be therapeutically effective as well andcan be substituted with ease.

Examples of useful testosterone and related compounds include withoutlimitation: testosterone, methyltestosterone, androstenedione,adrenosterone, dehydroepiandrosterone, oxymetholone, fluoxymesterone,methandrostenolone, testosterone, methyltestosterone, androstenedione,adrenosterone, dehydroepiandrosterone, oxymetholone, fluoxymesterone,methandrostenolone, testolactone, pregnenolone,17α-methylnortestosterone, norethandrolone, dihydrotestosterone,danazol, oxymetholone, androsterone, nandrolone, stanozolol,ethylestrenol, oxandrolone, bolasterone and mesterolone, testosteronepropionate, testosterone cypionate, testosterone phenylacetate,testosterone enanthate, testosterone acetate, testosterone buciclate,testosterone heptanoate, testosterone decanoate, testosterone caprate,testosterone isocaproate, and combinations thereof.

These testosterone compounds can be present in subsaturatedconcentrations, or low concentrations. Examples of compositionscomprising subsaturated testosterone are known in the art. See, forexample, U.S. Pat. Nos. 5,164,190, and 5,152,997, which are incorporatedby reference in their entirety. These testosterone compositions and/orother sex hormones, such as estrogen, progestin, etc. can also beprovided using carriers that are stable over long-term storage. Suchcompositions may comprise ethylhexylacrylate polymers, as described inU.S. Pat. No. 5,780,050, which is incorporated by reference herein.Methods for providing such hormones to males and females are also wellknown. See, U.S. Pat. Nos. 5,460,820, 5,152,997, and 5,783,208, whichare incorporated by reference in their entirety. It is appreciated thatusing the disclosure of the present invention, one skilled in the artcan readily accomplish the objective of the above-referenced patents.

Examples of useful estradiol and related compounds include withoutlimitation 17β-estradiol, 17α-estradiol, conjugated equine estrogen,esterified estrogen, micronized estradiol, sodium estrogen sulfate,ethinyl estradiol, estrone, tibolone, selective estrogen receptormodulator (SERM), phytoestrogen, and mixtures thereof. Examples ofuseful progestin and related compounds include without limitation:progesterone, medroxy-progesterone acetate, norethindrone, andnorethindrone acetate.

Examples of useful oxybutynin compounds include without limitation:N-desethyloxybutynin, (R)-oxybutynin, (S)-oxybutynin,(R)—N-desethyloxybutynin, and (S)—N-desethyloxybutynin. Particularly, ithas been noted that the oxybutynin metabolite, N-desethyloxybutynin, aswell as it (R)- and (S)-optical isomers exert an anticholinergic actionthat is equal to or greater than oxybutynin, and can be readilydelivered for such a purpose. See, U.S. Pat. Nos. 5,411,740, 5,500,222,5,532,278, 5,677,346, 5,686,097, 5,736,577, 5,747,065, 5,750,137, and5,900,250, which are incorporated by reference in their entirety.

Transdermal delivery of oxybutynin using triacetin as a penetrationenhancer has been described by U.S. Pat. Nos. 5,834,010, and 5,601,839,which are incorporated by reference in their entirety. Oxybutynin can beadministered in low concentrations, such that the serum concentrationsof one or more of its metabolites can be significantly lowered with thebeneficial effect of reduced adverse drug reactions, such asanticholinergic effects (including dry mouth, constipation, blurredvision, etc.).

Examples of propentofylline compositions, which can be used inconnection with the present invention, are described in U.S. Pat. No.5,762,953, which is incorporated by reference in its entirety. It isappreciated that the transdermal penetration of such compositions may befurther enhanced using the quaternary ammonium salt compounds of thepresent invention.

It is appreciated that any combination of any of the above drugs (thatis one or more of any of the above drugs) may be used in this invention.The present invention also contemplates the use of such salts, isomers,polymorphs, prodrugs, analogs, and metabolites, including substances notspecifically recited above.

It should also be recognized that the term “drug” as used herein refersto practically any chemical substance that has pharmacological activityor biological activity, as well as those substances that can be used fordiagnostic or cosmetic purposes. Thus, vitamins, such as vitamin A, C,E, K, and various B complexes, veterinary drugs, and cosmetic agentssuch as wrinkle-reducing agents (including anti-oxidants, for example,ascorbic acid, ascorbyl palmitate, catechins, an polyphenol compounds),depilating agents (including calcium salt, thioglycolic acid, andcalcium hydroxide), hair-growing agents (including relaxin, cyproteroneacetate, spironolactor, flutamide, and minoxidil), depigmenting agents(including sulfites, bisulfites, and metabisulfites, and alkaline earth,and alkaline earth metal compounds thereof), are also included. Further,the term “drug” includes peptides, proteins, carbohydrates, fats, etcthat are known to exert biological and or pharmacological effects.

It is appreciated that the above categories of drugs are not rigidlydescribed and that one drug may be described accurately in more than onecategory or sub-category. For example, insulin may be described as ahormone, as an anti-diabetic agent and also as a macromolecule.

Referring to FIGS. 7 and 8, another peelable pouch 80 in accordance withthe present invention is shown which is similar in many respects as thatdescribed above. The pouch 80 includes more than one set of tabs, suchas opposite first and second sets of tabs 84 and 86 formed on oppositesides of the pouch 80, so that the pouch can be opened from either side.

The pouches described above have rectangular or square shapes with foursides, while the seals form a pentagon shape or polygon with five sideswithin the perimeter of the rectangular shape of the pouch. Forming thefive sided polygon seal within the perimeter of the rectangular pouchcreates the tabs.

Referring to FIGS. 9 a-9 h, the pouch, seal, tabs, plies, and/or objectscontained in the pouch can have other shapes. For example, the pouch canbe shaped to conform to the shape of the object or patch containedtherein. The pouch can be round or oval to eliminate sharp corners, asshown in FIGS. 9 a-9 d. It will be appreciated that the thinness of theplies combined with corners can form sharp edges that can be reduced byusing round, oval, or curved pouches.

Referring to FIG. 9 a, the pouch 90 can be substantially or mostlyround, and have can have a substantially or mostly round seal 32. Aportion of the pouch 90 can extend beyond the round or circular shape toform the tabs 40 that extend outside the circular shape. Referring toFIG. 9 b, the pouch 91 and seal 32 similarly can be mostly round orcircular. A portion of the seal 32 can be indented into the circularshape to form tabs 40 that are within the circular shape.

Referring to FIG. 9 c, the pouch 93 can be substantially elliptical. Theseal 32 can be substantially circular, thus forming tabs 40 at thedistal ends of the elliptical pouch 93. Referring to FIG. 9 d, the pouch94 and seal 32 can be substantially elliptical. A portion of the seal 32can indented into the elliptical shape to form tabs 40 that are withinthe elliptical shape.

Referring to FIGS. 9 e and 9 f, the pouches can be triangular. Referringto FIG. 9 e, the pouch 95 and seal 32 can be substantially triangular. Aportion of the seal 32 can be indented into the elliptical shape to formtabs 40 that are within the triangular shape. Referring to FIG. 9 f, thepouch 96 can be triangular while the seal 32 can be circular to create aplurality of tabs 40 around the pouch. Such a configuration can beeasier to open because it can be opened from any corner of thetriangular pouch 96.

Referring to FIGS. 9 g and 9 h, the pouches can be a polygon, such as apentagon. Referring to FIG. 9 g, the pouch 97 and seal 32 can have apentagonal shape. A portion of the seal can be indented to form tabs 40within the pentagon. Referring to FIG. 9 h, the pouch 98 can bepentagonal, while the seal 32 is circular, to form a plurality of tabs40 about the pouch.

As illustrated in FIGS. 10 and 11, mechanisms are shown for packagingtransdermal patches into the peelable pouches as described above. Themechanisms can operate intermittently or continuously, and can beoriented horizontally or vertically. For example, the mechanism 100shown in FIG. 10 operates intermittently and is oriented horizontally,while the mechanism 110 shown in FIG. 11 operates continuously, and isoriented vertically. A method for packaging a transdermal patch 18 asdescribed above can utilize such mechanisms. Such a method includesplacing the transdermal patchs 18 between the first and second plies 22and 24. The plies can be provided in continuous rolls of stockmaterials, such as first and second rolls 114 and 116, disposed onpayouts of the mechanism. The rolls of material provide webs 118 betweenwhich, or upon which, the patches 18 can be disposed so that the patchesare placed between the first and second plies. The rolls of material canbe sized larger or wider than the actual pouches so that more than onepouch can be produced simultaneously by placing numerous patches betweenthe plies in a spaced apart relationship.

Referring to FIG. 10, the packaging can be oriented horizontally withthe webbing oriented horizontally so that the patches can be disposedonto one of the webs or plies. Thus, one of the rolls or payouts can bea lower roll or payout, while the other is an upper roll or payout.Alternatively, referring to FIG. 11, the packaging can be orientedvertically with the webbing oriented vertically so that the patches canbe disposed between the webs or plies.

Referring to FIG. 10, the patches can be provided stacked in a cartridge119 adjacent the webbing. One or more patches can be picked from thecartridge and placed on the web. Alternatively, referring to FIG. 11,the patches can be provided in a continuous roll 120 disposed on apayout of the mechanism. Individual patches can be separated or cut fromthe roll prior to the webbing, and placed thereon or therebetween. Themechanism can include a cutter with blades shaped to form the patches.The cutter can be a rolling cutter 122 with a cylindrical shape thatmakes rolling contact with the web to continuously cut or separate thepatches from the web.

With the patches disposed between the webs or plies, at least a portionof the webs or plies are sealed together to form the enclosures aboutthe patches. In one aspect, a seal is formed entirely around each patch.The plies are sealed by applying heat and pressure against the plies fora predetermined time period. The mechanisms can include a heat sealstation 132 in which a press is movably disposed to selectively contactthe plies. The press can be shaped and sized similar to a mold or blankof the seal. Thus, when the press contacts the plies, the seal is formedin the desired shape and size. The press can be configured to formnumerous seals at the same time.

As shown in FIG. 10, the press 132 can be applied against the plies in alinear motion. Thus, the heat and pressure can be applied intermittentlyby the press. Alternatively, as shown in FIG. 11, the press 134 can becylindrical and rotatably coupled to the mechanism to make rotatingcontact with the plies. Thus, the heat and pressure can be appliedcontinuously, and the webbing can be run continuously. The press canhave circular or arcuate molds or blanks of the seal formed therein.

Portions of the plies that extend beyond the seal or enclosure are leftunsealed in order to form the tabs. The numerous pouches can beseparated from one another and the webbing to form individual poucheswith individual patches therein. The mechanisms can include a shearingstation 150 for separating or cutting individual pouches from thewebbing. As shown in FIG. 10, the mechanism can include blades 152shaped and sized to cut the pouches from the webbing. The blades caninclude numerous blades to cut numerous pouches simultaneously. Theblades can contact the webbing or plies linearly, like a press. Thus,the blades can operate intermittently. Alternatively, as shown in FIG.11, the mechanism can include a cylindrical blade 154 rotatably coupledto the mechanism to make rolling contact with the webbing. Thus, thecylindrical blade can continuously cut the pouches from the webbing.

It is to be understood that the above-described arrangements are onlyillustrative of the application of the principles of the presentinvention. Numerous modifications and alternative arrangements may bedevised by those skilled in the art without departing from the spiritand scope of the present invention and the appended claims are intendedto cover such modifications and arrangements. Thus, while the presentinvention has been described above with particularity and detail inconnection with what is presently deemed to be the most practical andpreferred embodiments of the invention, it will be apparent to those ofordinary skill in the art that numerous modifications, including, butnot limited to, variations in size, materials, shape, form, function andmanner of operation, assembly and use may be made without departing fromthe principles and concepts set forth herein.

What is claimed is:
 1. A medicine system, comprising: 1) first andsecond opposing flexible plies forming an enclosure; 2) a seal,extending along at least a portion of a perimeter of the opposing plieswith an enclosed cavity between the plies; 3) first and second opposingtabs, formed by a portion of the respective first and second opposingplies which extend beyond the seal; 4) a transdermal matrix or liquidreservoir system patch, disposed in the enclosed cavity between thefirst and second opposing plies, comprising: a) a backing layer; b) acompound selected from the group consisting of: i) a salt oftestosterone; ii) methyltestosterone, androstenedione, adrenosterone,dehydroepiandrosterone, oxymetholone, fluoxymesterone,methandrostenolone, testolactone, pregnenolone, 17a-methylnortestosterone, norethandrolone, dihydrotestosterone, danazol,androsterone, nandrolone, stanozolol, ethylestrenol, oxandrolone,bolasterone, mesterolone, testosterone propionate, testosteronecypionate, testosterone phenylacetate, testosterone enanthate,testosterone acetate, testosterone buciclate, testosterone heptanoate,testosterone decanoate, testosterone caprate, testosterone isocaprateand combinations thereof; and iii) combinations thereof; c) an adhesivelayer with an exposed perimeter, wherein the adhesive layer comprises anadhesive; and d) a resilient release liner, removably attached over theadhesive layer so as to generate a spring force when displaced out ofthe flat configuration sufficient to overcome an adhesive force betweenthe patch and one of the plies created by the adhesive layer leaking anadhesive from the exposed perimeter onto one of the plies; the sealincluding a resin; and the first and second opposing flexible plieshaving: i) a closed configuration in which a majority of the two pliesare disposed in a planar layer; and ii) an open configuration in whichat least a portion of the two plies are separated along the seal andpulled out of the planar layer and back across the planar layer topresent the transdermal patch between the two plies.
 2. The medicinesystem of claim 1, wherein the first and second opposing flexible pliesform a pouch, and wherein the pouch comprises the enclosure.
 3. Themedicine system of claim 1, wherein the seal is formed by a processselected from the group consisting of chemical processes, mechanicalprocesses, ultra-sonic welding processes and combinations thereof. 4.The medicine system of claim 3, wherein the seal is formed by theapplication of one selected from the group consisting of heat, pressureand combinations thereof.
 5. The medicine system of claim 1, wherein theseal is corrugated, embossed or both.
 6. The medicine system of claim 1,wherein the seal extends along substantially the entire perimeter of theplies.
 7. The medicine system of claim 1, wherein a portion of the sealis indented from the perimeter of the plies.
 8. The medicine system ofclaim 1, wherein the first and second plies are formed from the same ora different sheet of material.
 9. The medicine system of claim 1,wherein at least one of the plies comprises an outer layer, a core layerand a laminate.
 10. The medicine system of claim 9, wherein at least oneof: (i) the outer layer comprises coated paper, (ii) the core layercomprises foil, and (iii) the laminate comprises low densitypolyethylene (LDPE).
 11. The medicine system of claim 1, wherein atleast one of the tabs is approximately the size of a fingertip.
 12. Themedicine system of claim 1, wherein the patch has a shape selected fromthe group consisting of rectangular, square, circular and oval.
 13. Themedicine system of claim 2, wherein the pouch has a shape selected fromthe group consisting of triangular, pentagonal, rectangular, square,round and oval.
 14. The medicine system of claim 1, wherein the backinglayer is at least one of opaque and occlusive.
 15. The medicine systemof claim 1, wherein the backing layer is selected from the groupconsisting of metal foils, metalized polyfoils, composite foils, filmscontaining polyester, polyester, aluminized polyester,polytetrafluoroethylene, polyether block amide copolymers, polyethylenemethyl methacrylate block copolymers, polyurethanes, polyvinylidenechloride, nylon, silicone elastomers, rubber-based polyisobutylene,styrene, styrene-butadiene copolymers, styrene-isoprene copolymers,polyethylene, polypropylene and combinations thereof.
 16. The medicinesystem of claim 1, wherein the release liner is selected from the groupconsisting of metal foils, metalized polyfoils, composite foils, filmscontaining polyester, polyester, aluminized polyester,polytetrafluoroethylene, polyether block amide copolymers, polyethylenemethyl methacrylate block copolymers, polyurethanes, polyvinylidenechloride, nylon, silicone elastomers, rubber-based polyisobutylene,styrene, styrene-butadiene copolymers, styrene-isoprene copolymers,polyethylene, polypropylene and combinations thereof.
 17. The medicinesystem of claim 1, wherein the adhesive layer includes at least one of apressure sensitive adhesive and a biocompatible polymer.
 18. Themedicine system of claim 17, wherein the pressure sensitive adhesive issuitable for contact with skin for a time period selected from the groupconsisting of a few minutes to a few hours, less than one day, one day,more than one day, about 3-4 days and about 1-4 weeks.
 19. The medicinesystem of claim 17, wherein the biocompatible polymer is a biocompatibleadhesive polymer.
 20. The medicine system of claim 1, wherein theadhesive is selected from the group consisting of acrylic adhesives,vinyl acetate adhesives, natural rubbers, synthetic rubbers,ethylenevinylacetate copolymers, polysiloxanes, polyacrylates,polyurethanes, plasticized weight polyether block amide copolymers,plasticized styrene-rubber block copolymers and combinations thereof.21. The medicine system of claim 20, wherein the adhesive is selectedfrom the group consisting of cross-linked acrylic copolymers,uncross-linked acrylic polymers, polyisobutylenes, neoprenes,polybutadienes, polyisoprenes and combinations thereof.
 22. The medicinesystem of claim 1, wherein the adhesive comprises hexamethyleneglycoldimethacrylate, 2-ethyl hexylacrylate and N-vinyl pyrrolidone.
 23. Themedicine system of claim 1, wherein the transdermal patch is a matrixpatch comprising a matrix, wherein the matrix comprises the compound.24. The medicine system of claim 1, wherein the transdermal patch is aliquid reservoir system patch comprising a reservoir, wherein thereservoir comprises the compound.
 25. The medicine system of claim 1,wherein the transdermal patch further comprises a permeation enhancer.26. The medicine system of claim 25, wherein the permeation enhancer isselected from the group consisting of fatty acids, fatty acid esters,fatty alcohols, fatty acid esters of lactic acid or glycolic acids andtheir salts, amides, amines, pyrrolidones, glycerol trimesters,terpenes, classical surfactants, azocyclic compounds, organic acids,complexing agents, biologics and mixtures thereof.